Abstract
Zika virus (ZIKV), a member of the Flaviviridae family, has emerged as a major public health threat, since ZIKV infection has been connected to microcephaly and other neurological disorders. Flavivirus genome replication is driven by NS5, an RNA-dependent RNA polymerase (RdRP) that also contains a N-terminal methyltransferase domain essential for viral mRNA capping. Given its crucial roles, ZIKV NS5 has become an attractive antiviral target. Here, we have used integrated structural biology approaches to characterize the supramolecular arrangement of the full-length ZIKV NS5, highlighting the assembly and interfaces between NS5 monomers within a dimeric structure, as well as the dimer-dimer interactions to form higher order fibril-like structures. The relative orientation of each monomer within the dimer provides a model to explain the coordination between MTase and RdRP domains across neighboring NS5 molecules and mutational studies underscore the crucial role of the MTase residues Y25, K28 and K29 in NS5 dimerization. The basic residue K28 also participates in GTP binding and competition experiments indicate that NS5 dimerization is disrupted at high GTP concentrations. This competition represents a first glimpse at a molecular level explaining how dimerization might regulate the capping process.
Highlights
Zika virus (ZIKV) is a mosquito-borne flavivirus, closely related to other important human pathogens such as Dengue (DENV), West Nile (WNV), Japanese encephalitis (JEV) and yellow fever viruses (YFV) [1]
The lack of vaccine or antiviral drugs to combat Zika virus (ZIKV) infection has encouraged scientists to characterize in depth potential drug targets
The structural and biophysical data presented in this work demonstrate that the ZIKV NS5 protein has the ability to form dimers, as well as higher order oligomers that may participate in the fine-tuning regulation of the multiple enzyme functions in the replication complex
Summary
Zika virus (ZIKV) is a mosquito-borne flavivirus, closely related to other important human pathogens such as Dengue (DENV), West Nile (WNV), Japanese encephalitis (JEV) and yellow fever viruses (YFV) [1]. First isolated in 1947 from a sentinel rhesus macaque in the Zika Forest region of Uganda [2], ZIKV remained neglected for many years until outbreaks occurred on Yap island in 2007 and within the French Polynesian islands in 2013–2014, before spreading across the Pacific Ocean and probably invading South America [3,4,5,6]. Contrasting the Yap island outbreak, which was characterized by cases with relatively mild dengue-like symptoms the outbreaks in French Polynesia and Brazil were associated with an unusual proportion of serious neurological disorders such as microcephaly in newborn infants [8] and Guillain-Barresyndrome in adults [9,10]. The understanding of how the different proteins and/or protein domains interact with each other to form functional complexes is still limited
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